The Role And Mechanism Of CHAF1A In Prostate Cancer Progression

Background:Currently,prostate cancer is the most common cancer in men and has the second highest mortality rate.Current treatment options have not prevented the progression of cancer.Therefore,exploring the development mechanism of prostate cancer is of great significance for improving the survival rate of prostate cancer patients.Chromatin assembly factor 1(CAF-1)is a highly conserved histone chaperone heterotrimer composed of p48,p60 and p150(CHAF1A)subunits.CAF-1 plays an important role in a variety of biological processes,such as chromatin maintenance after DNA repair.Existing studies have shown that CHAF1A can promote the progression of malignant tumors by regulating cell proliferation and the entry of histone variant H3.3 into chromosomes.Therefore,CHAF1Ais considered as an important oncogenic factor.Targeting CHAF1A is expected to become a new treatment strategy for malignant tumors,but its specific role and molecular mechanism in prostate cancer remain unclear.Purpose:This topic clarifies the expression level and effect of CHAF1A in prostate cancer,and to explore the molecular mechanism of CHAF1A promoting the progression of prostate cancer.Methods:This topic is divided into three parts.The first part is to clarify the expression of CHAF1A in prostate cancer cells and tissues,and discusses its correlation with the prognosis of prostate cancer patients:(1)The expression and clinical significance of CHAF1A in prostate cancer patients were analyzed using TCGA,GEO and cBioPortal databases.(2)The expression of CHAF1A in prostate cancer and adjacent tissues were detected using immunohistochemistry.(3)qRT-PCR and Western Blot were used to detect the expression level of CHAF1A in prostate cancer cells.The second part is to clarify the role of abnormally high expressed CHAF1A in the progression of prostate cancer:the silent expression and overexpression of CHAF1A were established,and the effects of different expression levels of CHAF1A on the proliferation,migration and invasion of prostate cancer cells were detected by CCK8,clonogenesis,EdU and Transwell experiments.The third part is to explore the mechanism of CHAF1A in the progression of prostate cancer:RNA-seq data obtained from RNAi interfering with the expression of CHAF1A in prostate cancer cells were used to analyze the potential downstream genes and pathways regulated by CHAF1A.The effects on ferroptosis,ferroptosis inducer HMOX1 and transcriptional regulatory molecule NRF2 were detected in CHAF1A silenced cells.Results:The first part showed that the expression of CHAF1A was up-regulated in prostate cancer cells and tissues,and was related to the malignancy of prostate cancer,and prostate cancer patients with abnormally high expression of CHAF1A had a poor prognosis.The second part showed that CHAF1A gene silencing could inhibit the proliferation,migration and invasion of prostate cancer cells,while the overexpression of CHAF1A could promote the proliferation,migration and invasion of prostate cancer cells.The third part showed that the silencing of CHAF1A could induce ferroptosis in prostate cancer cells,and HMOX1 was the ferroptosis driver with the most significant downstream expression change after the silencing of CHAF1A.The silent expression of CHAF1A can promote the expression of HMOX1 mRNA and protein,and the protein expression level of NRF2,the upstream transcription regulator of HMOX1.Conclusion:This study indicated that CHAF1A,as a candidate oncogene,can enhance the proliferation,migration and invasion of prostate cancer cells,promoting the progression of prostate cancer.Silencing CHAF1A can up-regulate the expression of NRF2 protein expression,and then transcriptionally regulate HMOX1 to increase its expression,thus inducing ferroptosis in prostate cancer cells.This study provides a new mechanism for the progression of prostate cancer,as well as new ideas and tactics for the treatment of prostate cancer.